There is a constant need for methods for the safe and effective administration of physiologically active agents, such as antifungal agents. For many medications it is important that the administration regime is as simple and non-invasive as possible in order to maintain a high level of compliance by a patient. Oral administration is one administration regime that is commonly used because it is a relatively simple regime to follow. However, the oral administration route is also complicated because of complications associated with gastrointestinal irritation and with drug metabolism in the liver. Adverse effects consisted of, liver damage, hepatic dysfunction, congestive heart failure (Ahmad S R et al, Lancet. 2001 Jun. 2; 357(9270):1766-7; Hay R J, J Am Acad Dermatol. 1993 Jul. 29(1):S50-4.; Chambers W M, Eur J Gastroenterol Hepatol. 2001 Sep. 13(9):1115-8), transient taste disturbance (Lemont H, Sabo M., J Am Podiatr Med Assoc. November-December 2001; 91(10):540-1), gastro disturbance and rashes (Roberts D T., Dermatology. 1997;194 Suppl 1:37-9.). Poor responsiveness and relapse of the oral therapy is also common (Roberts D T, Br J Dermatol (1999), 141 (suppl 5-6), 1-4; Tosti A et al, Dermatol (1998) 197, 162-166). As a number of the antifungal agents are potent inhibitors of cytochrome P450 (CYP) enzymes, drug-drug interactions may affect therapeutic outcome (Debruyne D, Coquerel A., Clin Pharmacokinet. 2001;40(6):441-72).
Administration of physiologically active agents through the skin (‘topical drug delivery’) has received increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow and controlled route for release of a physiologically active agent into the local tissue. Topically administered ciclopirox (Batrafen®, Aventis Pharma Ltd, Auckland, New Zealand) (Seebacher C, Nietsch K H, Ulbricht H M., Cutis. August 2001;68(2 Suppl):17-22; Gupta A K, Baran R, J Am Acad Dermatol. October 2000;43(4 Suppl):S96-102.), amorolfine (Loceryl®, Gladerma, Amersham, UK) (Zaug M et al, Clin Exp Dermatol, (1992) 17 (Sup 1): 61-70) and tioconazole (Trosyl®, Pfizer, Sandwich, UK) (Hay R J et al, Clin Exp Dermatol, (1985) 10:111-115) have demonstrated efficacy in treating nail fungal infection (onychomyosis) to some extent. Onychomycosis is known to affect the nail plate and nail bed. Topical agents capable of lateral diffusion into the infected areas would be beneficial. However, topical drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism.
Structurally, the skin consists of two principle parts, a relatively thin outermost layer (the ‘epidermis’) and a thicker inner region (the ‘dermis’). The outermost layer of the epidermis (the ‘stratum corneum’) consists of flattened dead cells which are filled with keratin. The region between the flattened dead cells of the stratum corneum is filled with lipids which form lamellar phases that are responsible for the natural barrier properties of the skin.
For effective local delivery of a physiologically active agent that is applied to the surface of the skin (‘topical application’), the agent must be partitioned firstly from the vehicle into the stratum corneum, it must typically then be diffused within the stratum corneum before being partitioned from the stratum corneum to the local tissues including the viable epidermis, dermis, subcutis and appendageal.
To overcome some of the problems with topical delivery that are associated with transport across the dermal layers (‘percutaneous absorption’), physiologically active agents are commonly formulated with incorporation of one or more dermal penetration enhancers (Finnin and Morgan, J. Pharm. Sci., Vol 88, No. 10, October 1999, pp. 755-758) which are often lipophilic chemicals that readily partition into the stratum corneum whereupon they exert their effects on improving the transport of drugs across the skin barrier.
There is a need for improved compositions for topical delivery of antifungal agents.